Targeting T790M mutation to improve NSCLC outcomes
Third-generation EGFR tyrosine kinase inhibitors (TKIs) designed to overcome the T790M mutation have been shown to double progression-free survival (PFS) of patients with advanced non-small-cell lung cancer (NSCLC) harbouring activating EGFR mutations, according to reports at the European Lung Cancer Conference (ELCC) 2016 held recently in Geneva, Switzerland.
“T790M mutations are observed in 50 to 60 percent of EGFR-mutant lung cancers with acquired resistance to first-generation TKIs. The third-generation pyrimidine-based, irreversible TKIs inhibit both EGFR activating and T790M resistance mutations, while sparing wild-type EGFR,” said Professor Tony Mok of the Chinese University of Hong Kong. “Osimertinib was the first of them to be granted accelerated approval in November 2015, having demonstrated impressive objective response rate [ORR] and PFS in T790M-positive patients.”
Mature results of the AURA studies, which investigated osimertinib at the recommended dose of 80 mg once daily in EGFR- and T790M-positive patients who had progressed on previous EGFR-TKI therapy, showed a response rate of 71 percent in the phase I dose-expansion cohort of 63 patients and 66 percent in pooled data of 411 patients from two phase II studies. Median PFS was 9.7 and 11 months, and the duration of response 9.6 and 12.5 months, respectively, with a good tolerability profile. [ELCC 2016, abstract LBA2_PR]
“The osimertinib data indicate that PFS can be extended by about 10 additional months beyond the 9 to 13 months achieved with conventional EGFR TKI inhibitors, which is unprecedented,” noted Mok.
Rociletinib, another T790M inhibitor under regulatory review, has demonstrated a response rate of 50-60 percent in patients who failed conventional EGFR TKIs. Phase III data are now awaited before the US FDA makes a ruling on approval because of toxicity signals such as QT prolongation and hyperglycaemia, which has been attributed to a metabolite of rociletinib.
“Other third-generation TKIs are also undergoing clinical trials. For example, HM61713 has entered a phase II trial, while RGF816 has shown a 75 percent ORR in a phase II study but has been associated with unusual macopapular rash,” said Mok. “Avitinib, which is structurally distinct from other third-generation TKIs, has shown an ORR of 36 percent in a phase I study.”
Despite the promise of third-generation TKIs, novel mechanisms of acquired resistance that evade T790M inhibition have been identified. According to Dr. Suresh Ramalingam of Emory University in Atlanta, GA, US, about 20 percent of T790M-positive tumours develop acquired EGFR C797S mutation and nearly 50 percent have loss of T790M at resistance. “Loss of T790M can be mediated by competing resistance mechanisms such as MET or HER2 amplification or BRAF V600E,” he explained. “Strategies to overcome resistance include the combination of third-generation TKIs with PD-L1 inhibitors or MEK inhibitors, while patients with slow progression can be continued on T790M inhibitors.”
In addition, third-generation TKIs are being evaluated as first-line therapy for advanced EGFR-positive NSCLC, omitting the first-line EGFR TKIs entirely. “Preliminary data seem encouraging. It makes sense to hit harder from the start to prevent resistance, as third-generation TKIs inhibit both EGFR activating mutations and de novo or secondary T790M resistance mutations,” suggested Dr. David Planchard of the Institute Gustave Roussy, Villejuif, France. “They also have a better tolerability profile and better brain penetration than conventional EGFR TKIs.”